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Atrial Fibrillation 1

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									Atrial Fibrillation 1

Atrial Fibrillation
Lawrence Rosenthal, MD, PhD, Associate Professor of Medicine, Director, Section of Cardiac
Electrophysiology and Pacing, Fellowship Director of Clinical Cardiac Electrophysiology, Department of
Internal Medicine, Division of Cardiovascular Medicine, University of Massachusetts Memorial Medical
Center
David D McManus, MD, Fellow, Cardiac Electrophysiology Section, University of Massachusetts Memorial
Medical Center
Nov 21, 2008

Introduction

Background
Atrial fibrillation (AF) is a supraventricular tachyarrhythmia characterized by disorganized atrial
electrical activity and progressive deterioration of atrial electromechanical function.
Electrocardiographic manifestations of atrial fibrillation include absence of P waves; rapid oscillations
(or fibrillatory [f] waves) that vary in amplitude, frequency, and shape; and an irregular ventricular
response.


Atrial fibrillation is the most common arrhythmia encountered in clinical practice and is a significant
public health problem in the United States. Atrial fibrillation affects more than 2.2 million Americans
and almost 5% of the population older than 69 years. The prevalence of atrial fibrillation increases
dramatically with age. Atrial fibrillation is associated with known cardiovascular risk factors such as
hypertension, coronary artery and valvular heart disease, heart failure (HF) and diabetes mellitus.1


Data from the Framingham heart study show that atrial fibrillation is associated with a 1.5- to 1.9-fold
higher risk of death, which is in part due to the strong association between atrial fibrillation and
thromboembolic events.2 While patients can be asymptomatic, many experience a wide variety of
symptoms, including palpitations, dyspnea, fatigue, dizziness, angina, and decompensated heart
failure. In addition, atrial fibrillation can be associated with hemodynamic dysfunction, tachycardia-
induced cardiomyopathy, and systemic thromboembolism.

Overall, approximately 15-25% of all strokes in the United States (75,000/y) can be attributed to atrial
fibrillation. Known risk factors for stroke in patients with atrial fibrillation include male sex, valvular
heart disease (rheumatic valvular disease), heart failure, hypertension, and diabetes. Additional risk
factors, such as advanced age and prior history of stroke, diabetes, and hypertension, place patients
with preexisting atrial fibrillation at even higher risk for further comorbidities such as stroke (see Table
1).3


Table 1. Risk Factors for Stroke in Patients with Nonvalvular Atrial Fibrillation



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Risk Factors                                                  Relative Risk

Prior stroke or TIA                                           2.5

History of hypertension                                       1.6

Heart failure and/or reduced left ventricular function 1.4

Advanced age                                                  1.4

Diabetes                                                      1.7

Coronary artery disease                                       1.5

Risk Factors                                                  Relative Risk

Prior stroke or TIA                                           2.5

History of hypertension                                       1.6

Heart failure and/or reduced left ventricular function 1.4

Advanced age                                                  1.4

Diabetes                                                      1.7

Coronary artery disease                                       1.5


Patients with rheumatic heart disease and atrial fibrillation have an even higher risk for stroke (17-fold).
At least 4 large clinical trials have clearly demonstrated that anticoagulation with warfarin decreases
the risk of stroke by 50-80%.
Unlike most cardiovascular diseases, the prevalence of atrial fibrillation is increasing in the United
States and worldwide. Atrial fibrillation is frequently encountered in both the inpatient and outpatient
settings. Primary therapeutic goals include rate control, maintenance of sinus rhythm, and prevention
of thromboembolism.


For related information, see Medscape's Cardiac Rhythm Management and Atrial Fibrillation Resource
Centers.

Pathophysiology
While the precise mechanisms that cause atrial fibrillation are incompletely understood, atrial fibrillation
appears to require both an initiating event and a receptive atrial substrate. Significant discoveries in
the last decade have highlighted the importance of focal pulmonary vein triggers, but alternative
hypotheses have been proposed. These include multiple wavelets, mother waves, fixed or moving
rotors, and macro-reentrant circuits. In a given patient, multiple mechanisms may be present at any
given time. The automatic focus theory and the multiple wavelet hypothesis appear to have the best
supportive data.


A focal origin of atrial fibrillation is supported by several experimental models showing that atrial
fibrillation persists only in isolated regions of atrial myocardium. This theory has garnered considerable
attention recently as studies have demonstrated that a focal source of atrial fibrillation can be identified
in humans and that isolation of this source can eliminate atrial fibrillation.


The pulmonary veins appear to be the most frequent source of these automatic foci, but other foci
have been demonstrated in several areas throughout the atria. Cardiac muscle in the pulmonary veins
appears to have active electrical properties similar, but not identical, to those of atrial myocytes.
Heterogeneity of electrical conduction around the pulmonary veins is theorized to promote reentry and
sustained atrial fibrillation. Thus, pulmonary vein automatic triggers may provide the initiating event
and heterogeneity of conduction may provide the sustaining event in many patients with atrial
fibrillation.

The multiple wavelet hypothesis proposes that fractionation of wavefronts propagating through the
atria results in self-perpetuating ―daughter wavelets.‖ In this model, the number of wavelets is
determined by the refractory period, conduction velocity, and mass of atrial tissue. In this model,
increased atrial mass, shortened atrial refractory period, and delayed intra-atrial conduction increase
the number of wavelets and promote sustained atrial fibrillation. This model is supported by data from
patients with paroxysmal atrial fibrillation demonstrating that widespread distribution of abnormal atrial
electrograms predicts progression to persistent atrial fibrillation.4 Intra-atrial conduction
prolongation has also been shown to predict recurrence of atrial fibrillation.5 Together, these data
highlight the importance of atrial structural and electrical remodeling in the maintenance of atrial
fibrillation.


Atrial fibrillation shares strong epidemiologic associations with other cardiovascular diseases such as
heart failure, coronary artery disease, valvular heart disease, diabetes mellitus and hypertension. 1
These factors have been termed upstream risk factors, but the relationship between comorbid
cardiovascular disease and atrial fibrillation is incompletely understood and more complex than this
terminology implies. The exact mechanisms via which cardiovascular risk factors predispose to atrial
fibrillation are not fully understood but are under intense investigation. Catecholamine excess,
hemodynamic stress, atrial ischemia, atrial inflammation, metabolic stress, and neurohumoral cascade
activation are all purported to promote atrial fibrillation.

Frequency
United States

Atrial fibrillation affects more than 2.2 million Americans. One in 4 individuals 40 years of age and older
will develop atrial fibrillation during their lifetime.6 Atrial fibrillation can occur in the absence of
comorbidities, as it does in 10-15% of cases of atrial fibrillation (lone atrial fibrillation). However, atrial
fibrillation is often associated with other cardiovascular diseases, including hypertension; heart failure;
diabetes; ischemic heart disease; and valvular, dilated, hypertrophic, restrictive, and congenital
cardiomyopathies.6
Atrial fibrillation can be triggered after cardiac surgery and is associated with pulmonary disease,
thyrotoxicosis, acute ethanol intoxication, and electrolyte imbalance. Given the almost epidemic
proportions of patients with atrial fibrillation, clinicians should be aware of the multiple mechanisms and
triggers for atrial fibrillation. Correcting the underlying disorder is often necessary to successfully treat
atrial fibrillation.

Mortality/Morbidity
Atrial fibrillation is associated with increased morbidity and mortality, in part due to the risk of
thromboembolic disease in atrial fibrillation. Disruption of normal atrial electromechanical function in
atrial fibrillation leads to blood stasis. This, in turn, can lead to development of thrombus, most
commonly in the left atrial appendage. Dislodgement of a clot can lead to embolic phenomena,
including stroke.


One of the major management decisions in atrial fibrillation (and atrial flutter) is determining the risk of
stroke and appropriate anticoagulation regimen for low-, intermediate-, and high-risk patients. For each
anticoagulant, the benefit in terms of stroke reduction must be weighed against the risk of serious
bleeding.


Most clinicians agree that the risk-benefit ratio of warfarin therapy in low-risk patients with atrial
fibrillation is not advantageous. Warfarin therapy has, however, been shown to be beneficial in high-
risk patients with atrial fibrillation. A target international normalized ratio (INR) of 2-3 is traditionally
used in this cohort as this is limits the risk of hemorrhage while providing protection against thrombus
formation. The appropriate treatment regimen for patients with atrial fibrillation at intermediate risk is
controversial. In this population, the clinician should assess risk factors for thromboembolic
disease, patient preference, risk of bleeding, risk of falls or trauma, and likelihood of medication
adherence.


Several risk factor assessment algorithms have been developed to aid the clinician in decision-making
regarding anticoagulation in atrial fibrillation. The CHADS2 index7 (Cardiac failure, Diabetes, Stroke [or
S2 = TIA]) is the most widely used of these algorithms. The CHADS2 index uses a point system to
determine yearly thromboembolic risk. Two points are assigned for a history of stroke or TIA, and one
point is given for age over 75 or a history of hypertension, diabetes, or heart failure. The predictive
value of this scoring system was evaluated in 1733 elderly patients with nonvalvular atrial fibrillation
aged 65-95 who were not given warfarin at hospital discharge. Although high scores were
associated with an increased rate of stroke, few patients had a score greater than 5 or a score of 0
(see Table 2).


Table 2. Adjusted Stroke Rate in Patients with Nonvalvular Atrial Fibrillation not Treated with
Anticoagulation

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CHADS2 Score Adjusted Stroke Rate (%/y)

0                   1.9

1                   2.8

2                   4.0

3                   5.9

4                   8.5

5                   12.5

6                   18.2

CHADS2 Score Adjusted Stroke Rate (%/y)

0                   1.9

1                   2.8

2                   4.0

3                   5.9

4                   8.5

5                   12.5

6                   18.2



Recommendations for anticoagulation for patients with nonvalvular atrial fibrillation are based on a
2006 ACC/AHA/ESC task force on the management of patients with atrial fibrillation 8 (see Table 3).


Table 3. Recommendations for Antithrombotic Therapy in Patients with Nonvalvular Atrial Fibrillation

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Risk Category                                             Recommended Therapy

No risk factors                                           Aspirin 81-325 mg daily

One moderate-risk factor                                  Aspirin 81-325 mg daily or warfarin (INR
                                                          2-3)
Any high-risk factor or more than 1 moderate-risk            Warfarin (INR 2-3)
factor

Risk Category                                                Recommended Therapy

No risk factors                                              Aspirin 81-325 mg daily

One moderate-risk factor                                     Aspirin 81-325 mg daily or warfarin (INR
                                                             2-3)

Any high-risk factor or more than 1 moderate-risk            Warfarin (INR 2-3)
factor



High-risk factors include prior stroke, TIA, and systemic thromboembolism.


Moderate-risk factors include age older than 75 years, hypertension, heart failure, left ventricular
function <35%, and diabetes mellitus.


Risk factors of unknown significance include female gender, age 65-74 years, coronary artery disease,
and thyrotoxicosis.

Age
Atrial fibrillation is strongly age-dependent, affecting 4% of individuals older than 60 years and 8% of
persons older than 80 years. The rate of ischemic stroke among elderly patients not treated with
warfarin averages approximately 5% per year.

Clinical

History
Initial evaluation of the patient with new-onset atrial fibrillation should focus on the patient's
hemodynamic stability. An effort should also be made to evaluate for potential comorbid diseases that
contribute to initiation or maintenance of atrial fibrillation. Immediate electrical cardioversion should be
considered for patients with hemodynamic collapse or evidence of cardiac ischemia.

        Initial history
              o    Clinical type of atrial fibrillation should be documented (paroxysmal, persistent, or
                   permanent)
              o    Type, duration, and frequency of symptoms should be assessed
              o    Precipitating factors should be assessed (ie, exertion, sleep, caffeine, alcohol use)
              o    Modes of termination should be assessed (ie, vagal maneuvers)
              o    Prior antiarrhythmics and rate-controlling agents used should be documented
              o    Presence of underlying heart disease should be assessed
              o    Any previous surgical or percutaneous atrial fibrillation ablation procedures should be
                   documented
Physical
The physical examination is helpful in determining underlying causes and sequelae of atrial fibrillation.
An initial examination of the patient with new-onset atrial fibrillation should attend particularly to their
hemodynamic stability.


        Vital signs - Heart rate, blood pressure, respiratory rate, and oxygen saturation are particularly
         important in evaluating hemodynamic stability and adequacy of rate control in atrial fibrillation.
        Head and neck - May reveal exophthalmos, thyromegaly, elevated jugular venous pressures,
         or cyanosis. Carotid artery bruits suggest peripheral arterial disease and increase the
         likelihood of comorbid CAD.
        Pulmonary - May reveal evidence of heart failure (ie, rales or pleural effusion). Wheezes or
         diminished breath sounds are suggestive of underlying pulmonary disease (ie, chronic
         obstructive pulmonary disease or asthma).
        Cardiac - The cardiac examination is central to the physical examination of the patient with
         atrial fibrillation. A displaced point of maximal impulse or S3 suggest ventricular enlargement
         and elevated left ventricular pressure. A prominent P2 points to the presence of pulmonary
         hypertension. Thorough palpation and auscultation are necessary to evaluate for valvular
         heart disease or cardiomyopathy.
        Abdomen - Ascites, hepatomegaly or hepatic capsular tenderness suggest right ventricular
         failure or intrinsic liver disease.
        Lower extremities - Examination of the lower extremities may reveal cyanosis, clubbing or
         edema. Assessment of peripheral pulses may lead to the diagnosis of peripheral arterial
         disease or diminished cardiac output.

Causes
Atrial fibrillation is strongly associated with established cardiovascular risk factors and advancing age.
Hypertension, diabetes, and coronary artery disease promote atrial fibrillation. Structural heart disease,
including valvular and congenital heart disease, is also associated with atrial fibrillation. Acute
pulmonary processes, acute or chronic alcohol use (ie, holiday or Saturday night heart, also known as
alcohol-related cardiomyopathy), illicit drug use (ie, stimulants, methamphetamines, cocaine) and
hyperthyroidism also increase the risk of atrial fibrillation. Patients undergoing cardiothoracic or
esophageal surgery are another population at risk for atrial fibrillation. In all, 20-40% of these patients
experience postoperative atrial fibrillation. Certain poorly defined genetic factors may also contribute to
an individual's propensity to develop atrial fibrillation.


        Hemodynamic stress: Increased intra-atrial pressure results in atrial electrical and structural
         remodeling and predisposes to atrial fibrillation. Mitral or tricuspid valve disease and left
         ventricular dysfunction are the most common causes of increased atrial pressure. Systemic or
         pulmonary hypertension also commonly predispose to atrial pressure overload. Intracardiac
         tumors or thrombi are rare causes of increased atrial pressure.
        Atrial ischemia: Coronary artery disease can infrequently lead directly to atrial ischemia and
         atrial fibrillation. More commonly, severe ventricular ischemia leads to increased intra-atrial
         pressure and atrial fibrillation.
        Inflammation: Myocarditis and pericarditis may be idiopathic or may occur in association with
         the following:
               o Collagen vascular diseases
               o Viral or bacterial infections
               o Cardiac, esophageal, or thoracic surgery
        Drug use: Stimulants, alcohol, and cocaine can trigger atrial fibrillation.
        Endocrine disorders: Hyperthyroidism and pheochromocytoma have been associated with
         atrial fibrillation.
        Neurologic: Intracranial processes such as subarachnoid hemorrhage or stroke can also
         precipitate atrial fibrillation.
        Familial atrial fibrillation: History of parental atrial fibrillation appears to confer increased
         likelihood of atrial fibrillation.9


Differential Diagnoses

Atrial Flutter
Atrial Tachycardia
Atrioventricular Nodal Reentry Tachycardia (AVNRT)
Paroxysmal Supraventricular Tachycardia
Wolff-Parkinson-White Syndrome

Other Problems to Be Considered
Digoxin toxicity
Hyperthyroidism
Pulmonary disease
Cardiac ischemia secondary to rapid ventricular rate

Workup

Laboratory Studies

        An electrocardiogram (ECG) should be obtained to establish the diagnosis of atrial fibrillation;
         look for pre-excitation; determine heart rate; and evaluate for left ventricular hypertrophy,
         bundle-branch block, or prior MI. The ECG is also useful to follow the QT and QRS intervals
         of patients receiving anti-arrhythmic medications for atrial fibrillation.
        Complete blood count, thyroid, hepatic, and renal function panels are often helpful, especially
         when ventricular rate is difficult to control.
        A toxicology screen or ethanol level may be appropriate to rule out acute intoxication.

Imaging Studies

        Transthoracic echocardiogram (TTE)
                 o   Evaluate for valvular heart disease
                 o   Evaluate atrial and ventricular chamber and wall dimensions
                 o   Estimate ventricular function and evaluate for ventricular thrombi
             o Estimate pulmonary systolic pressure (pulmonary hypertension)
             o Evaluate for pericardial disease
       Transesophageal echocardiogram (TEE)
             o Evaluate for left atrial (LA) thrombus (particularly in the LA appendage)
             o To guide cardioversion (if thrombus is seen, cardioversion should be delayed)
       Computed tomography (CT) or magnetic resonance imaging (MRI): If atrial fibrillation ablation
        is planned, then 3-dimensional imaging technologies (CT scan or MRI) are often helpful to
        evaluate atrial anatomy. Imaging data can be processed to create anatomic maps of the left
        atrium and pulmonary veins.
       Chest radiography: May help evaluate lung parenchyma and pulmonary vasculature in the
        appropriate clinical context.

Other Tests

       Electrocardiogram
             o    ECG findings usually confirm the diagnosis of atrial fibrillation.
             o    The ventricular rate is typically irregular.
             o    Discrete P waves are absent; instead, undulating fibrillatory (f) waves are present
                  (see Media file 1).
       Six-minute walk test or exercise test
             o    Six-minute walk or exercise testing can help assess the adequacy of rate control.
             o    Exercise testing can exclude ischemia prior to treatment of patients with Class Ic
                  drugs and can be used to reproduce exercise-induced atrial fibrillation.
       Holter monitoring or event recording: Helpful to establish diagnosis and evaluate rate control.
       Electrophysiology study
             o    May help identify the mechanism of a wide-QRS-tachycardia.
             o    May help identify a predisposing arrhythmia.
             o    May help identify sites for curative ablation or AV node ablation.

Procedures
Electrical cardioversion


       Direct-current (DC) cardioversion is synchronized to the R wave to prevent a shock from being
        delivered during the vulnerable phase of the T wave. This reduces the likelihood of inducing
        ventricular fibrillation.
       Elective DC cardioversion is used to restore sinus rhythm if patients are anticoagulated
        adequately with a therapeutic international normalized ratio (INR) and remain in atrial
        fibrillation.
       In most patients, the procedure can be performed safely in an outpatient setting.
       Administration of either moderate sedation (according to sedation guidelines) or general
        anesthesia is necessary for patient comfort and safety during elective atrial fibrillation
        cardioversion.
      Defibrillating patches can be positioned in several locations, including the right anterior and
       left posterior positions. This position allows the defibrillation vector to include the atria.
       Standard placement in the anterior and lateral positions is also acceptable.
      A high initial success rate should be expected. Some patients remain in sinus rhythm only
       transiently and quickly revert back to atrial fibrillation. If initially unsuccessful, check patch
       placement and consider use of an anti-arrhythmic such as ibutilide (see Medication section) to
       reduce the defibrillation threshold and increase the likelihood of cardioversion. Use of
       defibrillators with biphasic waveforms have consistently been demonstrated to be more
       efficacious in converting atrial fibrillation to sinus rhythm.10
      Patients with atrial fibrillation of less than 48 hours' duration may be considered for immediate
       cardioversion as the risk of thromboembolic sequelae from cardioversion in these patients is
       small.
      If the precise duration of the atrial fibrillation cannot be determined or if duration of atrial
       fibrillation is longer than 48 hours, TEE should be used to guide cardioversion. Alternatively, if
       the patient is able to tolerate atrial fibrillation, anticoagulation for 4 weeks can circumvent the
       need for TEE prior to cardioversion.
      Regardless of long-term anticoagulation strategy or duration of atrial fibrillation, administration
       of anticoagulation with heparin or enoxaparin is recommended prior to cardioversion.
      Body habitus and urgency can be used to guide shock energy. An obese patient with a large
       anteroposterior diameter will probably require higher energy (ie, 360 J monophasic). A thinner
       person may require lower energy (200 J). Required energies are always lower with biphasic
       waveforms (100-200 J).
      Two sets of patches can be used to successfully cardiovert patients in whom a single maximal
       shock with 1 set of patches fails. Two external defibrillators and 2 sets of defibrillation patches
       are required. Vectors are crossed so that 1 set of patches is placed anteriorly left of the
       sternum and posteriorly right of the spine. The second set of patches is placed anteriorly right
       of the sternum and posteriorly left of the spine. The 2 defibrillators may be activated
       simultaneously, in synchronized fashion, or with a slight delay after the first discharge. This
       method may succeed when a single set of patches fails.
      Internal cardioversion is also possible but must be performed in the electrophysiologic
       laboratory. Intracardiac catheters can be positioned in the right atrium and in the coronary
       sinus. Synchronized shocks are then delivered between the 2 catheters, with energies from 1-
       100 J. Alternatively, a defibrillating current may be passed between a single intracardiac
       catheter (right atrium, coronary sinus) and a single cutaneous patch placed anteriorly or
       posteriorly.

Chemical cardioversion


      Hemodynamically stable patients with atrial fibrillation can be converted to sinus rhythm using
       oral or intravenous agents. Oral dosing of Class Ic agents [flecainide (300 mg) or propafenone
       (450-600 mg)] has been shown to be efficacious in patients with atrial fibrillation of shorter
       duration (<7 d).11 These drugs require monitoring for side-effects (ie, ventricular tachycardia
       and heart failure). Coadministration of an AV-nodal blocking agent (ie, beta-blocker or
       nondihydropyridine calcium channel blocker) is generally recommended to prevent conversion
       to atrial flutter with rapid ventricular response.
        While inpatient loading of Class Ic agents is not required for those without structural heart
         disease, it is frequently practiced. Use of flecainide and propafenone is contraindicated in
         patients with structural heart disease (left ventricular hypertrophy or prior myocardial
         infarction), baseline QRS or QT prolongation (QTc longer than 460 ms) or in those receiving
         concomitant antiarrhythmic therapy.
        Intravenous procainamide (Class Ia, <18 mg/kg/h) or ibutilide (Class III, 1 mg over 15 m) may
         also be used for chemical cardioversion of atrial fibrillation or to increase likelihood of
         successful electrical cardioversion. Both of these agents should only be used in a highly
         monitored, inpatient setting. These drugs predispose to ventricular tachycardia and they
         should not be used in those with significant structural heart disease, QT prolongation, or
         electrolyte abnormalities. Some clinicians preadminister magnesium to attempt to reduce the
         risk of ventricular tachycardia. Frequent monitoring of blood pressure, heart rate, and
         telemetry are advised.
        Oral dosing of other Class III agents (dofetilide, amiodarone) may also be used for chemical
         cardioversion or to increase the likelihood of successful electrical cardioversion. Sotalol is not
         generally recommended for chemical cardioversion. Amiodarone can be initiated as an
         outpatient in the appropriate clinical context (in patients without structural heart disease or
         other comorbidities). Initiation of dofetilide must be performed as an inpatient. Amiodarone
         and dofetilide are efficacious in patients with structural heart disease, including those with
         prior myocardial infarction or heart failure. Monitoring for bradycardia, electrolyte disturbances
         and QT prolongation is strongly recommended.

Staging
Several classification schemas have been proposed for the study of atrial fibrillation, but none fully
accounts for all aspects of atrial fibrillation. A number of different labels and nomenclature have been
used to describe patterns of atrial fibrillation, including acute, chronic, paroxysmal, intermittent, and
permanent. The vagaries of each of these definitions make comparing the results of studies assessing
the magnitude and treatment of atrial fibrillation difficult.

Published guidelines from expert committees of the American College of Cardiology/American Heart
Association and European Society of Cardiology on the treatment of patients with atrial fibrillation
suggest that atrial fibrillation be classified into 3 patterns (see Media file 2). These include a first
detectable episode, irrespective of whether it is symptomatic or self-limited, also recognizing that there
may be some uncertainty about the duration of the episode and any prior undetected episodes.
Recurrent atrial fibrillation is considered to be present when a patient has 2 or more episodes of atrial
fibrillation. If atrial fibrillation terminates spontaneously, then recurrent atrial fibrillation is designated as
paroxysmal; if this arrhythmia becomes sustained, then atrial fibrillation is considered persistent
(irrespective of whether atrial fibrillation is terminated with pharmacologic therapy or electrical
cardioversion).

Persistent atrial fibrillation may be either the first presentation of atrial fibrillation or the result of
recurrent episodes of paroxysmal atrial fibrillation. Patients with persistent atrial fibrillation also include
patients with long-standing atrial fibrillation in whom cardioversion has not been indicated or
attempted, often leading to permanent atrial fibrillation. Permanent atrial fibrillation is recognized as the
accepted rhythm, and the main treatment goals are rate control and anticoagulation. While it is
possible to reverse the progression from paroxysmal to persistent and to permanent, this task can be
challenging.




Classification scheme for patients with atrial fibrillation.




This classification schema pertains to cases that are not related to a reversible cause of atrial
fibrillation (eg, thyrotoxicosis, electrolyte abnormalities, acute ethanol intoxication). The occurrence of
atrial fibrillation secondary to acute myocardial infarction, cardiac surgery, pericarditis, pulmonary
embolism, or acute pulmonary disease is considered separately because, in these situations, atrial
fibrillation is less likely to recur once the precipitating condition has been resolved and adequately
treated.
Some patients with paroxysmal atrial fibrillation, typically younger patients, have been found to have
distinct electrically active foci within their pulmonary veins. These patients generally have many atrial
premature beats noted on Holter monitoring. Isolation or elimination of these foci can lead to
elimination of the trigger for paroxysms of atrial fibrillation.

Patients can also have atrial fibrillation as a secondary arrhythmia associated with cardiac disease that
affects the atria (eg, congestive heart failure, hypertensive heart disease, rheumatic heart disease,
coronary artery disease). These patients tend to be older, and atrial fibrillation is more likely to be
chronic. Paroxysmal atrial fibrillation may progress to permanent atrial fibrillation, and aggressive
attempts to restore and maintain sinus rhythm may prevent comorbidities associated with atrial
fibrillation.

Persistent atrial fibrillation with an uncontrolled, rapid ventricular heart rate response can cause a
dilated cardiomyopathy and can lead to electrical remodeling in the atria (atrial cardiomyopathy).
Therapy, such as drugs or atrioventricular nodal ablation and permanent pacemaker implantation, to
control the ventricular rate can improve left ventricular function and improve quality-of-life scores.

New developments aimed at curing atrial fibrillation are being actively explored. By reducing the critical
mass required to sustain atrial fibrillation with either surgical or catheter-based compartmentalization of
the atria (ie, MAZE procedure), fibrillatory wavelets collide with fixed anatomic obstacles, such as
suture lines or complete lines of ablation, thus eliminating or reducing the chance of chronic atrial
fibrillation. Some patients with focal origins of their atrial fibrillation also may be candidates for catheter
ablation. Still, much remains to be accomplished before either of these procedures is appropriate for
primary treatment.
Treatment

Medical Care
Management of New-Onset Atrial Fibrillation
The management of atrial fibrillation can be broken down into management of new-onset and long-
standing atrial fibrillation. The cornerstones of new-onset atrial fibrillation management are rate control
and anticoagulation.12 The clinical decision to use a rhythm control or rate control strategy requires
integration of several factors, including degree of symptoms, likelihood of successful cardioversion and
presence of comorbidities. Anticoagulation is an important consideration in both new onset and long-
standing atrial fibrillation.




Patient management for newly diagnosed atrial fibrillation. Subtherapeutic INR:
INR <2 for 3 consecutive weeks. Warfarin: INR target 2-3. TEE/cardioversion:
low molecular weight heparin 1 mg/kg bid as a bridge with initiation of warfarin
INR 2-3.




Restoration of sinus rhythm with regularization of the heart's rhythm improves cardiac hemodynamics
and exercise tolerance. By maintaining the atrial contribution to cardiac output, symptoms of heart
failure and overall quality of life can improve. As atrial fibrillation contributes to pathologic atrial and
ventricular remodeling, restoration of sinus rhythm can slow and, in some cases, reverse atrial
dilatation and left ventricular dysfunction. For these reasons, most clinicians focus initially on
maintenance of sinus rhythm and opt for a rate control strategy only when rhythm control fails.
However, several randomized controlled trials have demonstrated that a strategy aimed at restoring
(and maintaining) sinus rhythm neither improves the survival rate nor reduces the risk of stroke
in patients with atrial fibrillation.


In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study,13 4060
subjects aged 65 years or older whose atrial fibrillation was likely to be recurrent and who were at risk
for stroke were randomized to a strategy of rhythm control (cardioversion to sinus rhythm plus drugs to
maintain sinus rhythm) versus a strategy of rate control (in which no attempt was made to restore or
maintain normal sinus rhythm). An insignificant trend toward increased mortality was noted in the rate
control group, and, importantly, no evidence suggested that the rhythm control strategy protected
patients from stroke. Clinically silent recurrences of atrial fibrillation in the rhythm control group are
theorized to be responsible for the increased rates of thromboembolic events and mortality noted in
this cohort. This underscores the importance of anticoagulation in both rhythm control and rate control
patients.


The AFFIRM study (and similar findings from the smaller Rate Control Versus Electrical Cardioversion
[RACE] trial14) has led to the development of consensus guidelines that recommend an initial rate-
control strategy for many asymptomatic patients with atrial fibrillation. The ACC/AHA/ESC 2006
guidelines state that an initial rate control strategy is "reasonable" for asymptomatic or minimally
symptomatic older patients with hypertension and comorbid cardiovascular disease.3 These same
guidelines state that for younger individuals, especially those without significant comorbid
cardiovascular disease, an initial rhythm control strategy may be a better approach.

Rate control


Regardless of long-term strategy chosen, control of ventricular rate is a critical component of
management of new-onset atrial fibrillation. The main determinants of the ventricular rate during atrial
fibrillation are those intrinsic and extrinsic factors that influence atrioventricular (AV) conduction.
Foremost among these are the intrinsic AV nodal conduction properties. Underlying sympathetic and
parasympathetic tone also influences AV nodal conduction. Rate-controlling agents primarily act by
increasing AV nodal refractoriness.

           Beta-blockers and calcium channel blockers are first-line agents for rate control in atrial
            fibrillation. These drugs can be administered either intravenously or orally. They are effective
            at rest and with exertion. Caution should be exercised in patients with reactive airway disease
            who are given beta-blockers.
           Digoxin can be used in the acute setting but does little to control the ventricular rate in active
            patients. As such, it is rarely used as monotherapy. Caution should be exercised in elderly
            patients and those with renal failure receiving digoxin. Digoxin is indicated in patients with
            heart failure and reduced LV function.
           Amiodarone has a Class IIa recommendation from the ACC/AHA/ESC for use as a rate
            controlling agent for patients who are intolerant of or unresponsive to other agents. Caution
            should be exercised in those not receiving anticoagulation as amiodarone can promote
            cardioversion.

Anticoagulation


Atrial fibrillation is recognized as a powerful risk factor for stroke. One of the most important
considerations in the acute management of atrial fibrillation is the need for anticoagulation. Acute
cardioversion for atrial fibrillation carries a risk of thromboembolism unless anticoagulation therapy is
initiated prior to the procedure and continued post-procedure. Risk of thromboembolism in patients
undergoing either pharmacologic or electrical cardioversion is similar. The risk of thromboembolic
events is greatest when atrial fibrillation has been present for longer than 48 hours.

Effective anticoagulation in patients with atrial fibrillation reduces the risk of stroke 3-fold. Patients with
newly diagnosed atrial fibrillation and patients awaiting electrical cardioversion can be started on
intravenous heparin (activated partial thromboplastin time [aPTT] of 45-60 s) or low molecular weight
heparin (1 mg/kg bid).

Patients can be concomitantly started on warfarin in an inpatient setting while awaiting a therapeutic
INR value (2-3). Many practices have developed specialized anticoagulation clinics to closely monitor
INR values.


Cardioversion


Cardioversion may be performed electively or emergently to restore sinus rhythm in patients with new-
onset atrial fibrillation. Cardioversion is most successful when initiated within 7 days after to onset of
atrial fibrillation. The need for cardioversion may be acute when atrial fibrillation is responsible for
hypotension, heart failure, or angina.


Pharmacologic agents or direct current energy can be used to cardiovert patients with atrial fibrillation.
Pharmacologic cardioversion has the advantage of not requiring sedation or anesthesia, but the major
disadvantage is the risk of ventricular tachycardia and other serious arrhythmias.

Long-Term Management of Atrial Fibrillation
Long-term management of atrial fibrillation is focused on reducing the likelihood of atrial fibrillation
recurrence, reducing atrial fibrillation-related symptoms, control of ventricular rate, and reducing stroke
risk. As discussed previously, atrial fibrillation often results from exposure to established
cardiovascular risk factors. Appropriate management of these risk factors will reduce the likelihood of
future atrial fibrillation and atrial fibrillation—related morbidity and mortality. Anticoagulation should be
initiated for all individuals with atrial fibrillation with either aspirin or warfarin except those with "lone"
atrial fibrillation or contraindications. Selection of the appropriate antithrombotic drug should be based
on the risk of stroke and bleeding for a given patient. Antiarrhythmic therapy can aid in maintenance of
sinus rhythm in certain patients but requires close monitoring.


Decision-making with regard to the optimal long-term strategy for atrial fibrillation management should
be based on a thorough integration of patient-specific factors and likelihood of success. As a rule,
younger patients with more severe symptoms and fewer comorbidities tend to derive a greater benefit
from a long-term focus on rhythm control. Older patients with structural heart disease (ie, left
ventricular hypertrophy, prior myocardial infarction, depressed ejection fraction, or atrial dilation) are
less likely to remain in sinus and are more likely to have serious side-effects from antiarrhythmic drugs.
In this cohort, most clinicians focus on long-term rhythm control.


Atrial fibrillation causes electrophysiologic and structural remodeling which, in turn, promotes future
atrial fibrillation ("atrial fibrillation begets atrial fibrillation"). As such, many patients with paroxysmal
atrial fibrillation will progress to persistent and permanent atrial fibrillation. The degree to which this
reflects the continuing influence of underlying cardiovascular risk factors as opposed to a direct effect
of atrial fibrillation is unknown. Regardless, clinicians frequently need to reevaluate their management
strategies as atrial fibrillation burden and comorbidities increase with time.
Anticoagulation


The goal of long-term anticoagulation in atrial fibrillation is to reduce the risk of thromboembolism.

        Patients in atrial fibrillation have a risk of stroke or peripheral embolism that is approximately 5
         times that of people in sinus rhythm.
        Recommendations for anticoagulation for patients with nonvalvular atrial fibrillation are based
         on a 2006 ACC/AHA/ESC task force on the management of patients with atrial fibrillation.8

Rate control


As discussed previously, several trials have validated the noninferiority of an initial rate-control
strategy. Many clinicians believe, however, that an attempt at a rhythm control strategy should be
made in most patients. Older patients with comorbid cardiovascular disease have a lower likelihood of
successful long-term rhythm control and thus these patients are often managed using a rate-control
strategy. Some patients initially managed with a rhythm control strategy will experience progression to
recurrent or persistent atrial fibrillation. Clinicians often switch to a rate control strategy as the atrial
fibrillation burden increases.

        AV nodal blocking medications are the cornerstone of rate control in long-standing atrial
         fibrillation. In the absence of an accessory pathway, oral beta-blockers, nondihydropyridine
         calcium channel blockers, and digoxin are effective. Generally, coadministration of beta-
         blockers and calcium channel blockers is reserved for patients in whom adequate rate control
         cannot be achieved using a single agent.
        Digoxin can be effective in sedentary patients (especially in those with heart failure) but
         requires close monitoring of drug levels and renal function.
        In the presence of tachycardia-mediated cardiomyopathy or inadequate ventricular rate
         control despite drug therapy, AV nodal ablation and pacemaker implantation can be
         considered.

Every effort should be made to assess effectiveness of rate control both at rest and with exertion,
especially in those patients who primarily experience exertional atrial fibrillation-related
symptoms. Twenty-four hour Holter monitoring or exercise-treadmill testing can be helpful in evaluating
heart rate variability. Adequate rate control can be defined as a heart rate of 60-80 bpm at rest and 90-
115 bpm with moderate exercise.

Rhythm control


Maintenance of sinus rhythm requires treatment of cardiovascular risk factors and any underlying
disorder (ie, hyperthyroidism) that may have triggered atrial fibrillation. As discussed previously,
several antiarrhythmic drugs (flecainide, propafenone, dofetilide, amiodarone) have established
efficacy in the pharmacologic conversion of atrial fibrillation to sinus rhythm. Several distinct agents,
most notably sotalol, are used for the long-term maintenance of sinus rhythm. Sotalol is efficacious
but, like other Class III drugs, requires close monitoring of the QT interval and serum electrolytes.
Unlike dofetilide and amiodarone, sotalol is contraindicated in patients with structural heart disease
and heart failure.


Catheter ablation is a reasonable alternative to pharmacologic therapy to prevent recurrent atrial
fibrillation in symptomatic patients with little or no structural heart disease.15 Catheter ablation is
currently being performed in select centers for persistent atrial fibrillation but this has not been
established as standard of care. Surgical ablation of atrial fibrillation is also an option for patients with
atrial fibrillation undergoing other cardiac surgery and in those patients in whom pharmacologic and
catheter-based procedures are ineffective or contraindicated.


New medical and device-based rhythm control therapies are being actively explored. Experimental and
clinical data suggest that renin-angiotensin system (RAS) antagonists and HMG-CoA-Reductase
Inhibitors (statins) may decrease the incidence of atrial fibrillation and increase the likelihood of
successful cardioversion.16, 17, 18, 19 Device-based therapies under research include single- and dual-site
atrial pacemakers to prevent atrial fibrillation and atrial defibrillators to rapidly restore sinus rhythm.
Invasive (surgical and catheter-based) therapies to compartmentalize the atria and localize focal
triggers (in the pulmonary veins) are being evaluated and refined. (see Surgical Care.)


Special considerations


Postoperative atrial fibrillation is common and perioperative beta-blockers are recommended in all
patients undergoing cardiac surgery unless contraindicated.20 Preoperative administration of
amiodarone and sotalol may reduce the incidence of atrial fibrillation in patients undergoing cardiac
surgery. As such, these agents may be used as prophylactic therapy in those at high risk for
postoperative atrial fibrillation.


Retrospective data suggest that atrial-based pacing (AAI, DDD modes) reduces the risk of developing
atrial fibrillation and increases the interval between episodes in patients with sick sinus syndrome. 21
Surgical Care
Since its inception, surgical compartmentalization of the atria, or the MAZE procedure, has evolved as
an exciting procedure with a potential to cure atrial fibrillation. Quite simply, the atria are transected
and resutured to reduce the critical mass required for the maintenance of atrial fibrillation. Early
experience shows that atrial transport is restored postoperatively and that long-term anticoagulation is
not required. The downside remains the need for an open chest procedure; however, thoracoscopic
procedures may reduce hospitalization and recovery times in the future. The surgical MAZE procedure
remains an attractive procedure for patients with atrial fibrillation who are undergoing concomitant
mitral valve procedures. Its role as a primary therapy for atrial fibrillation is doubtful. Catheter ablation
has taken the following 3 paths in the attempt to cure or manage atrial fibrillation.

        Compartmentalization of the atria with continuous ablation lines of block
              o      Parallel to the surgical MAZE procedure, electrophysiologists are attempting to
                     recreate surgical suture lines with radiofrequency lesions.
              o      The procedures tend to last many hours, and the success rates are somewhat
                     disappointing (50-60%), with left atrial reentrant tachycardias and left atrial flutters
                     appearing (requiring further ablation procedures).22
             o    Researchers are unsure which areas of the atria are necessary to sustain atrial
                  fibrillation. Purely right-sided lesions are not sufficient to eliminate atrial fibrillation,
                  making left atrial procedures necessary. In addition, gaps in linear lesions can be
                  difficult to find.
             o    Research currently focuses on catheter design to deliver linear continuous lesions.
                  Additionally, alternative energy sources (ie, cooling, LASER, ultrasonography) may
                  improve one's ability to deliver transmural lesions in the left atrium.
        Catheter ablation of focal triggers of atrial fibrillation
             o    In some patients, atrial fibrillation seems to be triggered by electrically active
                  pulmonary vein foci. These foci can trigger the atria to fibrillate.23
             o    Patients typically have an abundance of ectopic atrial beats noted on 24-hour Holter
                  monitoring. Electrical isolation of individual pulmonary veins, and thus the ectopic
                  foci, is performed successfully at many centers, and patient selection is key to
                  success. A combined procedure including individual pulmonary vein isolation, as well
                  as left atrial ablation (ie, encircling pulmonary vein pairs, connecting right and left
                  pairs along the left atrial roof, and connection to the mitral valve annulus) is often
                  necessary. The use of chest CT or MRI can be used to recreate 3-dimensional
                  anatomy in the left atrium, thus aiding in mapping and creating contiguous lines in the
                  left atrium. In addition, multiple procedures are often necessary.
             o    Complications are generally in the 5% range and include pulmonary vein stenosis
                  (that can be symptomatic), perforation, thromboembolism, and tamponade. Still, cure
                  rates as high as 70-80% have been reported in properly selected patients (patients
                  with frequent atrial premature beats and episodes of paroxysmal atrial fibrillation).
        Atrioventricular node ablation and insertion of a permanent pacemaker
             o    AV node ablation may represent an alternative in patients with chronic atrial
                  fibrillation and an uncontrolled ventricular response despite aggressive medical
                  therapy.
             o    Catheter ablation of the AV junction permanently interrupts conduction from the atria
                  to the ventricles.
             o    Because the result is permanent AV block, a permanent pacemaker is required. atrial
                  fibrillation may still exist, but the pacemaker governs the ventricular response.
             o    The risk of thromboembolism is unchanged, and patients still require anticoagulation;
                  however, most patients are relieved of their symptoms.
             o    During the first 1-3 months, the pacing rate must be programmed in the 80- to 90-
                  beat range to prevent TdP, which has been reported in the literature, presumably due
                  to slow ventricular rates and the occurrence of early after-depolarizations.
             o    Improvements in LV size and function, functional class, and quality-of-life scores
                  have been demonstrated.24

Consultations
Consultation with a cardiac electrophysiologist or knowledgeable clinician is recommended prior to
antiarrhythmic drug initiation.

Diet
Diet restrictions, if any, are as appropriate for the underlying heart disease and any other comorbidities
(eg, diabetes mellitus).

Medication

The goals of medical therapy for patients with atrial fibrillation are to maintain sinus rhythm, avoid the
risk of complications (eg, stroke), and minimize symptoms. Warfarin represents the cornerstone of
anticoagulant therapy for patients at moderate to high-risk of thromboembolic events. The goal of
antiarrhythmic drug therapy is to reduce the duration and frequency of atrial fibrillation episodes, thus
improving patient quality of life and symptoms. If successful, rhythm control can eliminate or delay the
need for long-term anticoagulation with warfarin in some patients.

Several antiarrhythmic drugs are commonly used to prevent atrial fibrillation recurrence. Currently, the
FDA has approved 5 antiarrhythmic drugs (quinidine, flecainide, propafenone, sotalol, dofetilide) for
the treatment of atrial fibrillation. Other antiarrhythmic agents (eg, amiodarone) are used in an off-label
fashion with great clinical efficacy. Use of antiarrhythmic drugs requires caution because they are
proarrhythmic. These agents can exacerbate pre-existing arrhythmias and generate arrhythmia de
novo. Tachy- and brady-arrhythmias generated by these agents can be of ventricular or atrial origin.
Drug-drug interactions and extra-cardiac side effects are common. Consultation with a cardiac
electrophysiologist or knowledgeable clinician is recommended prior to antiarrhythmic drug initiation.

If maintenance of sinus rhythm is the goal, the ACA/AHA/ECC have jointly developed guidelines for
the long-term antiarrhythmic treatment in the maintenance of sinus rhythm.3 The following algorithm
incorporates clinical trial data on the safety and efficacy of antiarrhythmic agents. These guidelines are
intended to help clinicians tailor antiarrhythmic therapy on an individual basis for their patients.


For patients with no evidence of structural heart disease, flecainide, propafenone and sotalol should be
considered first-line agents. Amiodarone or dofetilide can be considered as alternative agents. For
patients with substantial left ventricular hypertrophy (LVH), amiodarone is considered a reasonable
first-line agent. For patients with coronary artery disease, dofetilide or sotalol are first-line therapy.
Amiodarone is considered a second-line agent in this population. For patients with heart failure,
amiodarone or dofetilide are first-line agents.




Antiarrhythmic drug algorithm for the medical management of sinus rhythm in
patients with atrial fibrillation.
    Current practice constraints mandate that clinicians carefully consider patient populations at low and
    acceptable risks for outpatient antiarrhythmic drug initiation. Proarrhythmia is the most common
    adverse effect of antiarrhythmics during the loading phase. While the proarrhythmic effect of these
    drugs extends into the maintenance phase, inpatient drug initiation is generally recommended in the
    monitored inpatient setting, especially for those patients with structural heart disease or substantial
    comorbidities. Nevertheless, certain antiarrhythmic drugs have established and acceptable safety
    profiles when used in outpatients without structural heart disease or other risk factors.
    Atrioventricular nodal conduction blockers
    Used to slow ventricular response by slowing AV nodal conduction during atrial fibrillation or atrial
    flutter. Also indicated for use in conjunction with class IA and IC antiarrhythmics, which slow atrial
    fibrillation/flutter rate and may cause more rapid ventricular response.



    Esmolol (Brevibloc)

    Ultra–short-acting. Selectively blocks beta1-receptors with little or no effect on beta2-receptor types.
    Particularly useful in patients with elevated arterial pressure, especially if surgery is planned. Shown to
    reduce episodes of chest pain and clinical cardiac events compared with placebo. Can be discontinued
    abruptly if necessary. Useful in patients at risk for experiencing complications from beta-blockade,
    particularly those with reactive airway disease, mild-moderate LV dysfunction, and/or peripheral
    vascular disease. Short half-life of 8 min allows for titration to desired effect and quick discontinuation if
    needed.

             Dosing
             Interactions
             Contraindications
             Precautions
    Adult

    250-500 mcg/kg/min for 1 min loading dose followed by a 4 min maintenance infusion of 50
    mcg/kg/min


    If adequate therapeutic effect not observed within 5 min, repeat loading dose and follow with
    maintenance infusion using increments of 50 mcg/kg/min (for 4 min); sequence may be repeated up to
    4 times prn


    As the desired heart rate approached, omit loading infusion and reduce incremental dose of
    maintenance infusion from 50 mcg/kg/min to 25 mcg/kg/min or lower; interval between titration steps
    may be increased from 5 min to 10 min if needed

    Pediatric
    Not established; 100-500 mcg/kg administered over 1 min suggested
            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Propranolol (Inderal)

    Class II antiarrhythmic, nonselective, beta-adrenergic receptor blocker with membrane-stabilizing
    activity that decreases automaticity of contractions.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    1-3 mg (under careful monitoring) IV; not to exceed 1 mg/min IV to avoid lowering blood pressure and
    causing cardiac standstill
    Allow time for drug to reach site of action (particularly if slow circulation); administer second dose after
    2 min prn; thereafter, do not administer additional drug after desired alteration in rate or rhythm
    achieved; switch to 10-160 mg PO bid

    Pediatric

    2-4 mg/kg/d PO divided bid (1-2 mg/kg bid)
    IV use not recommended; however, for arrhythmias, 0.01-0.1 mg/kg, not to exceed 1 mg/dose, by slow
    push has been recommended; change to PO as soon as possible

            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Atenolol (Tenormin)

    Selectively blocks beta-1 receptors with little or no effect on beta-2 types. Esmolol is excellent for use
    in patients at risk for experiencing complications from beta-blockade, particularly those with reactive
    airway disease, mild-to-moderate LV dysfunction, and/or peripheral vascular disease. Short half-life of
    8 min allows for titration to desired effect and quick discontinuation if needed.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    Up to 200 mg PO qd

    Pediatric

    Not established

            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions
    Metoprolol (Lopressor)

    Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During IV
    administration, carefully monitor blood pressure, heart rate, and ECG.

           Dosing
           Interactions
           Contraindications
           Precautions
    Adult

    5 mg IV for 3 doses q2-5 min; then up to 200 mg PO bid

    Pediatric

    Not established

           DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Digoxin (Lanoxin)

    Slows sinus node and AV node via vagomimetic effect and not very effective if sympathetic tone is
    increased. Generally not recommended unless depressed LV function is present.

           Dosing
           Interactions
           Contraindications
           Precautions
    Adult

    Loading dose: 1.5-2 mg PO/IV in divided dose over 1-2 d
    Maintenance dose: 0.25 mg PO/IV qd

    Pediatric

    Premature neonates: 15-25 mcg/kg PO/IV divided into 3 or more doses (first dose equalling half total
    dose), then remaining doses q6-8h; maintenance of 4-6 mcg/kg/d PO/IV divided bid
    Neonates: 20-30 mcg/kg PO/IV divided into 3 or more doses (first dose equalling half total dose), then
    remaining doses q6-8h; maintenance of 5-8 mcg/kg/d PO/IV divided bid
    <2 years: 30-50 mcg/kg PO/IV divided into 3 or more doses (first dose half total dose), then remaining
    doses q6-8h; maintenance of 7.5-12 mcg/kg/d PO/IV divided bid
    2-5 years: 25-35 mcg/kg PO/IV divided into 3 or more doses (first dose equalling half total dose), then
    remaining doses q6-8h; maintenance of 6-9 mcg/kg/d PO/IV divided bid
    6-10 years: 15-30 mcg/kg PO/IV divided into 3 or more doses (first dose equalling half total dose), then
    remaining doses q6-8h; maintenance of 4-8 mcg/kg/d PO/IV divided bid
    >10 years: 8-12 mcg/kg PO/IV divided into 3 or more doses, (first dose equalling half total dose), then
    remaining doses q6-8h; maintenance of 2-3 mcg/kg/d PO/IV qd
            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautionsAntiarrhythmics,            class IA
    Quinidine, procainamide, and disopyramide are IA antiarrhythmic agents used to maintain sinus
    rhythm. Generally, start administration in hospital because of high risk of adverse effects. All patients
    treated with class IA agents should be treated concomitantly with AV nodal blocking agents. Some
    patients demonstrate a slowing in atrial rate and an increase in AV conduction with rapid ventricular
    rates when treated with IA agents alone. Fading as first-line drugs for atrial fibrillation.



    Quinidine (Cardioquin, Quinalan, Quinidex, Quinaglute)

    Of Vaughn-Williams class IA agents, only quinidine is FDA-approved for atrial fibrillation. As with all
    class IA agents, QRS and QTc prolongation are main ECG manifestations. Should not be used in
    patients with a prolonged QTc baseline (>460 milliseconds). Generally has fallen out of favor as a first-
    or second-line agent for treatment of atrial fibrillation.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    300 mg PO q8-12h
    324 mg PO q8h of quinidine gluconate formulation

    Pediatric

    Not established

            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Procainamide (Procanbid, Pronestyl)

    Not FDA-approved for treatment of atrial fibrillation; however, many use this agent for acute
    cardioversion (eg, postoperatively) and because it can be administered IV. Administered IV, useful for
    acute conversion and can subsequently be converted to oral dose. Negative inotropic agent and
    vasodilator, and care must be taken in administering to patients with reduced LV function. Generally
    considered second-line agent.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult
    1000-2500 mg PO q12h (Procanbid formulation) based on body weight and normal renal function; not
    to exceed 18 mg/kg over 1 h with initial infusion
    Procainamide and N -acetyl procainamide (NAPA) levels should be drawn after steady state reached

    Pediatric

    Not established

            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Disopyramide (Norpace)

    Not commonly used to treat atrial fibrillation because it has adverse anticholinergic effects and
    because it is a strongly negative inotropic agent, which may precipitate CHF and cardiogenic shock in
    patients with reduced LV function. May be useful in vagally mediated syncope.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    150 mg PO q6h
    300 mg PO q12h (CR formulation)

    Pediatric

    <12 years: 6-20 mg/kg/d PO divided q6h
    >12 years: Administer as in adults

            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautionsAntiarrhythmics,            class IC
    Indicated for patients with atrial fibrillation and supraventricular tachycardia without structural heart
    disease. Given the results of the CAST I and II trials (increased mortality), type IC agents are generally
    not used in patients with concomitant LV dysfunction and/or CAD. Applicability of CAST results to
    other populations (eg, patients without recent MI) is uncertain. Many specialists initiate class IC
    antiarrhythmic agents in an outpatient setting for patients with paroxysmal atrial fibrillation and no
    associated structural heart disease. Regardless, close patient follow-up is mandated, with frequent
    ECG monitoring or via transtelephonic monitoring for potential signs of proarrhythmia.



    Propafenone (Rythmol)

    Shortens upstroke velocity (phase 0) of monophasic action potential. Reduces fast inward current
    carried by sodium ions in Purkinje fibers and, to a lesser extent, myocardial fibers. May increase
    diastolic excitability threshold and prolong effective refractory period. Reduces spontaneous
    automaticity and depresses triggered activity.
    Indicated for documented life-threatening ventricular arrhythmias, such as sustained ventricular
    tachycardia. Appears to be effective in treatment of supraventricular tachycardias, including atrial
    fibrillation and flutter. Not recommended in patients with less severe ventricular arrhythmias, even if
    symptomatic. Use in conjunction with AV nodal blocking agents when given to patients in atrial
    fibrillation because conversion to AFL with 1:1 conduction (producing fast ventricular rates) has been
    noted.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    150-300 mg PO tid
    225, 325, 425 mg PO bid (SR formulation)

    Pediatric

    Not established

            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Flecainide (Tambocor)

    Blocks sodium and potassium channels, producing dose-related decrease in intracardiac conduction in
    all parts of heart. Increases electrical stimulation of threshold of ventricle, His-Purkinje system.
    Shortens phase 2 and 3 repolarization, resulting in decreased action potential duration and effective
    refractory period.
    Indicated for treatment of paroxysmal atrial fibrillation/flutter associated with disabling symptoms and
    paroxysmal supraventricular tachycardias, including AV nodal reentrant tachycardia, AV reentrant
    tachycardia, and other supraventricular tachycardias of unspecified mechanism associated with
    disabling symptoms in patients without structural heart disease. Also indicated for prevention of
    documented life-threatening ventricular arrhythmias (eg, sustained ventricular tachycardia). Not
    recommended in less severe ventricular arrhythmias even if patients are symptomatic. Use in
    conjunction with AV nodal blocking agents when given to patients in atrial fibrillation because
    conversion to AFL with 1:1 conduction (producing fast ventricular rates) can occur.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    50-150 mg PO bid

    Pediatric

    Not established
              DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautionsAntiarrhythmics,               class III
    Currently, class III antiarrhythmic agents sotalol and dofetilide are FDA-approved for use in treating
    atrial arrhythmias; however, amiodarone is also widely used in maintenance of sinus rhythm in patients
    with atrial fibrillation. Dofetilide must be initiated in an inpatient setting. Sotalol is also initiated in an
    inpatient setting.



    Amiodarone (Cordarone)

    Has antiarrhythmic effects that overlap all 4 Vaughn-Williams antiarrhythmic classes. Has a low risk of
    proarrhythmia, and any proarrhythmic reactions generally are delayed. Used in patients with structural
    heart disease. Most clinicians are comfortable with inpatient or outpatient loading with 400 mg PO tid
    for 1 wk because of low proarrhythmic effect, followed by weekly reductions with goal of lowest dose
    with desired therapeutic benefit (usual maintenance dose for atrial fibrillation is 200 mg/d). During
    loading, patients must be monitored for bradyarrhythmias.

              Dosing
              Interactions
              Contraindications
              Precautions
    Adult

    400 mg PO tid for 1 wk, followed by weekly reductions (goal of lowest dose with desired therapeutic
    benefit)
    Maintenance for atrial fibrillation: 200 mg/d

    Pediatric

    Not established

              DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Sotalol (Betapace atrial fibrillation)

    Class III agent with beta-blocking effects. Effective in maintenance of sinus rhythm, even in patients
    with underlying structural heart disease. Inpatient loading is FDA-mandated.

              Dosing
              Interactions
              Contraindications
              Precautions
    Adult

    80 mg PO bid initially, with therapeutic goal of 120-160 mg PO bid

    Pediatric
    Not established

               DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Dofetilide (Tikosyn)

    Approved by FDA for maintenance of sinus rhythm as well as for the conversion of atrial fibrillation to
    sinus rhythm (approx 50%) in patients with persistent atrial fibrillation. Has no effect on cardiac output,
    cardiac index, stroke volume index, or systemic vascular resistance in patients with ventricular
    tachycardia, mild to moderate CHF, angina, and either normal or reduced LVEF. No evidence of
    negative inotropic effect.

               Dosing
               Interactions
               Contraindications
               Precautions
    Adult

    125, 250, or 500 mcg PO bid; must be started in a monitored inpatient setting for 3 days by certified
    clinician
    Dose determined by creatinine clearance (CrCl) and QTc response to initial doses

    Pediatric

    Not established

               DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Ibutilide (Corvert)

    Indicated for conversion of recent-onset atrial fibrillation or atrial flutter (3 h to 90 d). Prolongs
    repolarization by increasing slow inward sodium current and by blocking delayed rectifier current with
    rapid onset.

               Dosing
               Interactions
               Contraindications
               Precautions
    Adult

    >60 kg (132 lb): 1 mg IV infusion over 10 min
    <60 kg: 0.01 mg/kg IV over 10 min; second infusion of equal strength can be given 10 min after first
    prn
    Magnesium infusion (2 g MgSO4) has been used to pretreat patients receiving ibutilide to prevent TdP

    Pediatric
    Not established
            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautionsAnticoagulants

    Used to prevent thromboembolic complications.



    Heparin

    Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively
    lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous
    fibrinolysis. Most data related to use of unfractionated heparin. Low–molecular-weight heparin can also
    be utilized

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    60 U/kg IV initially, followed by maintenance infusion of 12 U/kg/h IV; target aPTT is 50-70 seconds

    Pediatric

    50 U/kg IV initially, followed by a maintenance infusion of 15-25 U/kg/h IV; increase dose by 2-4 U/kg/h
    q6-8h prn, using aPTT results

            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Enoxaparin Sodium (Lovenox)

    Low molecular weight heparin. Augments activity of antithrombin III and prevents conversion of
    fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents
    reaccumulation of clot after spontaneous fibrinolysis.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    1 mg/kg given as a sub cuticular injection bid assuming normal renal function;
    kinetics in patients more than 100 kg not well studied

    Pediatric

    May be used for thromboembolic disorders
    In a pilot study, 23 consecutive pediatric patients at an increased risk of bleeding with heparin were
    treated with subcutaneous enoxaparin 1 mg/kg q12h with subsequent doses adjusted to achieve a 4-
    hour anti-factor Xa level between 0.5-1 unit/mL for various thrombotic diseases. Six of the 7 infants (<2
    mo) required (based on anti-factor Xa levels) an average dose of 1.64 mg/kg bid. 3 children required a
    dose reduction to 0.5 mg/kg bid. Duration of treatment ranged from 10 days or less to more than 60
    days. Thrombotic events were deep vein thrombosis, pulmonary embolism, and thrombotic
    complication in the CNS. No new thrombotic events occurred and 2 patients, with previous diagnosed
    gastrointestinal ulcers, experienced bleeding that required transfusion

            DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosin
    gInteractionsContraindicationsPrecautions

    Warfarin (Coumadin)

    Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and
    treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor dose to
    maintain INR of 2-3.

            Dosing
            Interactions
            Contraindications
            Precautions
    Adult

    1-20 mg/d PO qd, adjust dose to desired INR (2-3) for nonvalvular atrial fibrillation/flutter

    Pediatric

    0.05-0.34 mg/kg/d PO; adjust dose according to weight and desired INR

    Follow-up

    Further Inpatient Care

            Monitor INR values of patients on warfarin (desired range 2-3). Attention to drug-drug
             interactions (particularly with amiodarone) is necessary.
            Monitor patients on antiarrhythmic agents for signs of proarrhythmia. Worsening liver or renal
             function can alter antiarrhythmic drug clearance and may require altered antiarrhythmic drug
             dosing. Careful monitoring of heart rate, blood pressure, and for physical signs of congestive
             heart failure is necessary. The QTc interval is also an important predictor of proarrhythmic
             events in patients on type IA and III agents.
            Monitor liver function, thyroid function, and lung function in patients treated with amiodarone.

    Further Outpatient Care

            Assessment and reassessment of thromboembolic risk is necessary.
            Periodic ECG monitoring (especially when taking antiarrhythmics) and Holter monitoring are
             often necessary to assess for paroxysmal atrial fibrillation and/or rate control.

    Deterrence/Prevention
       Experimental and clinical data suggest that renin-angiotensin system (RAS) antagonists and
        HMG-CoA reductase inhibitors (statins) may decrease the incidence of atrial fibrillation and
        increase the likelihood of successful cardioversion.10, 11, 12, 13
       Fish oil preparations have been shown to reduce ventricular arrhythmias in at-risk populations
        (coronary artery disease) and may also protect against atrial fibrillation.
       Treatment of underlying cardiovascular risk factors such as hypertension, coronary artery
        disease, valvular heart disease, obesity, sleep apnea, diabetes, and heart failure is likely to
        decrease the incidence of atrial fibrillation.

Prognosis

       Epidemiologic studies have shown that individuals in sinus rhythm live longer than do
        individuals with atrial fibrillation. The AFFIRM trial addressed whether rate control and
        anticoagulation are sufficient goals for asymptomatic, elderly patients. The results showed
        that medical therapies aimed at rhythm control offered no survival advantage over rate control
        and anticoagulation.
       Atrial fibrillation likely mediates this effect on overall prognosis through its association with
        thromboembolic events, particularly stroke.
       Development of atrial fibrillation predicts heart failure and is associated with worse NYHA HF
        class.
       Atrial fibrillation may cause tachycardia-mediated cardiomyopathy if adequate rate control is
        not established. Atrial fibrillation may also worsen heart failure in individuals who are
        dependent on the atrial component of the cardiac output. Those with hypertensive heart
        disease and those with valvular heart disease are particularly at high risk for developing heart
        failure when atrial fibrillation occurs.

Patient Education
For excellent patient education resources, visit eMedicine's Heart Center and Stroke Center. Also, see
eMedicine's patient education articles Atrial Fibrillation, Heart Rhythm Disorders, Stroke, and
Supraventricular Tachycardia.

Miscellaneous

Medicolegal Pitfalls

       Proper anticoagulation is extremely important in both paroxysmal and persistent atrial
        fibrillation.
       Anticoagulation before and after cardioversion is necessary.
       Use of antiarrhythmic agents requires regular, drug-specific follow-up testing.

Special Concerns

       Warfarin is contraindicated during pregnancy.
   Give special consideration to patients who are noncompliant and patients who are at risk for
    falling. These patients may be better off with antiplatelet agents such as aspirin.

								
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